An important focus of my work is development of chimeric antigen receptor T cell therapies for multiple myeloma, which is a usually incurable malignancy of plasma cells. A major obstacle to development of CAR-expressing T-cell therapies for multiple myeloma is the lack of suitable target antigens. Anti-BCMA CARs: I have recently designed and constructed two CARs that specifically recognize B-cell maturation antigen (BCMA). BCMA has a very restricted expression pattern in normal tissues, but BCMA is expressed on the malignant plasma cells of multiple myeloma.7 The BCMA specific CARs that I have constructed specifically recognize multiple myeloma cell lines in functional assays in vitro. Anti-BCMA CAR-expressing T cells can eradicate myeloma tumors in mice. An extensive analysis of BCMA expression in normal human tissues by immunohistochemistry and quantitative PCR has been conducted. Except for expression by normal plasma cells, BCMA expression was not detected in nomal human organs by immunohistochemistry. a paper and an abstract on this project have been published in the past year. A clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma has been opened for enrollment within the past month. No patient has yet been treated, but many patients are screening for the protocol, and interest among physicians is high. Other CARs targeting multiple myeloma: In addition to developing anti-BCMA CARs, I aim to develop CARs that target other antigens that are expressed by multiple myeloma cells but not normal essential tissues. Some promising candidate antigens have been identified, and initial evaluation of these antigens has begun. A new phase I trial of an anti-BCMA CAR opened in September, 2014. So far 8 patients have been treated and are evaluable for response. One patient obtained a PR, and one patient obtained a very good PR. Toxicity of patients on this trial has been mild. In conjunction with Bluebird Bio, Inc. We have developed a new anti-BCMA CAR that Bluebird licensed from the NCI. This new CAR was developed in part in my laboratory. This new CAR will be tested in a multicenter trial of which I will participate starting in the fall of 2015. In addition to these clinical and translational activities, a main focus of my lab is determing how to optmally design CARs. We have a project looking at how changes in the structure of the hinge region of CARs can be quite important in determining in vivo efficacy of CARs. We have been focusing on improving the structure of an anti-BCMA CAR over the past year, and great progress has been made in determining the optimal hinge region of anti-BCMA CARs.